Pubmed du 09/01/19

mercredi 9 janvier 2019

1. Avni E, Ben-Itzchak E, Zachor DA. The Presence of Comorbid ADHD and Anxiety Symptoms in Autism Spectrum Disorder : Clinical Presentation and Predictors. Frontiers in psychiatry. 2018 ; 9 : 717.

High rates of attention deficit/hyperactivity disorder (ADHD) and anxiety symptoms have been documented in autism spectrum disorder (ASD), and have been associated with social and adaptive impairments. The study examined the frequency of clinically elevated ADHD and anxiety symptoms in an ASD group in comparison to a non-clinical group, compared the clinical presentation in the ASD group with and without ADHD and anxiety, assessed which child and familial variables add to the severity of Inattention, Hyperactivity/Impulsivity (HI), and anxiety symptoms, and evaluated whether having clinically elevated ADHD and/or anxiety symptoms adds to the prediction of adaptive functioning in ASD. The study included 260 participants diagnosed with ASD (mean age : 7.5 +/- 1.1), using standardized tests. The rate of clinically elevated ADHD and anxiety symptoms in ASD was 62.7 and 44.6%, respectively, and symptom severity was significantly greater than the non-clinical sample. The entire population was divided into four subgroups : ASD alone, ASD+ADHD, ASD+anxiety, ASD+ADHD+anxiety, based on the parental behavioral questionnaire. The ASD alone group showed less severe autism symptoms in comparison to the other groups. Having ASD+ADHD symptoms was associated with greater impairments in socialization adaptive skills. Only the group with ASD+ADHD+anxiety was associated with poorer daily living adaptive skills. Regression analyses for prediction of ADHD and anxiety symptoms revealed that being a female and having lower adaptive skills scores predicted higher Inattention severity ; being older, having better cognition, and more severe Restrictive Repetitive Behavior symptoms predicted more severe HI symptoms ; being older and having more severe social impairments predicted higher anxiety scores. A regression analysis for the prediction of adaptive skills revealed that in addition to cognition and autism severity, the severity of Inattention symptoms added to the prediction of overall adaptive skills. In light of these findings, clinicians should diagnose these comorbidities in ASD early on, and provide effective interventions to reduce their negative impact on functioning, thereby improving outcome.

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2. Bejno H, Roll-Pettersson L, Klintwall L, Langh U, Odom SL, Bolte S. Cross-Cultural Content Validity of the Autism Program Environment Rating Scale in Sweden. J Autism Dev Disord. 2019.

Increasing rates of autism spectrum disorder (ASD) and younger age at diagnosis pose a challenge to preschool intervention systems. In Sweden, most young autistic children receive intervention service in community-based preschool programs, but no tool is yet available to assess the quality of the preschool learning environment. This study adapted the Autism Program Environment Rating Scale Preschool/Elementary to Swedish community context (APERS-P-SE). Following translation and a multistep modification process, independent experts rated the content validity of the adaptation. Findings indicate high cross-cultural validity of the adapted APERS-P-SE. The cultural adaption process of the APERS-P-SE highlights similarities and differences between the American and Swedish preschool systems and their impact on early ASD intervention.

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3. Bernardo P, Raiano E, Cappuccio G, Dubbioso R, Bravaccio C, Vergara E, Peluso S, Manganelli F, Esposito M. The Treatment of Hypersalivation in Rett Syndrome with Botulinum Toxin : Efficacy and Clinical Implications. Neurology and therapy. 2019.

INTRODUCTION : Subjects with Rett syndrome (RS) develop invariably severe motor deterioration resulting in swallowing difficulties that may produce excessive drooling. Hypersalivation can cause discomfort due to hygienic problems and may complicate with oral and respiratory dysfunctions. The aim of this study is to evaluate the response to treatment with botulinum toxin (BTX) for hypersalivation and to identify possible benefits of saliva reduction on oral motor and respiratory disorders of patients with RS. METHODS : Five consecutive patients with RS and hypersalivation were treated with incobotulinumtoxin A injected in salivary glands with ultrasound guidance. Severity of excessive drooling was assessed with the Thomas-Stonell and Greenberg Scale (TGSC) and the clinical impact of the treatment was evaluated using three selected items of RS Assessment Rating Scale (R.A.R.S.) : eating habits, dyspnoea and bruxism. Scale rating was performed before BTX injection (T0), 4 (T1) and 12 (T2) weeks after. RESULTS : Scores of TGSC and R.A.R.S. (for eating and bruxism) were reduced significantly after therapy at T1. CONCLUSIONS : BTX treatment for sialorrhea in RS is effective in reducing saliva production and may also improve oral motor functions.

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4. Biffi E, Costantini C, Ceccarelli SB, Cesareo A, Marzocchi GM, Nobile M, Molteni M, Crippa A. Gait Pattern and Motor Performance During Discrete Gait Perturbation in Children With Autism Spectrum Disorders. Front Psychol. 2018 ; 9 : 2530.

Quantitative evaluation of gait has been considered a useful tool with which to identify subtle signs of motor system peculiarities in autism spectrum disorder (ASD). However, there is a paucity of studies reporting gait data in ASD as well as investigating learning processes of locomotor activity. Novel advanced technologies that couple treadmills with virtual reality environments and motion capture systems allows the evaluation of gait patterns on multiple steps and the effects of induced gait perturbations, as well as the ability to manipulate visual and proprioceptive feedbacks. This study aims at describing the gait pattern and motor performance during discrete gait perturbation of drug-naive, school-aged children with ASD compared to typically developing (TD) peers matched by gender and age. Gait analysis was carried out in an immersive virtual environment using a 3-D motion analysis system with a dual-belt, instrumented treadmill. After 6 min of walking, 20 steps were recorded as baseline. Then, each participant was exposed to 20 trials with a discrete gait perturbation applying a split-belt acceleration to the dominant side at toe-off. Single steps around perturbations were inspected. Finally, 20 steps were recorded during a post-perturbation session. At baseline, children with ASD had reduced ankle flexion moment, greater hip flexion at the initial contact, and greater pelvic anteversion. After the discrete gait perturbation, variations of peak of knee extension significantly differed between groups and correlated with the severity of autistic core symptoms. Throughout perturbation trials, more than 60% of parameters showed reliable adaptation with a decay rate comparable between groups. Overall, these findings depicted gait peculiarities in children with ASD, including both kinetic and kinematic features ; a motor adaptation comparable to their TD peers, even though with an atypical pattern ; and a motor adaptation rate comparable to TD children but involving different aspects of locomotion. The platform showed its usability with children with ASD and its reliability in the definition of paradigms for the study of motor learning while doing complex tasks, such as gait. The additional possibility to accurately manipulate visual and proprioceptive feedback will allow researchers to systematically investigate motor system features in people with ASD.

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5. Bottema-Beutel K, Kim SY, Crowley S, Augustine A, Kecili-Kaysili B, Feldman J, Woynaroski T. The stability of joint engagement states in infant siblings of children with and without ASD : Implications for measurement practices. Autism Res. 2019.

Obtaining stable estimates of caregiver-child joint engagement states is of interest for researchers who study development and early intervention in young children with autism spectrum disorder (ASD). However, studies to date have offered little guidance on the numbers of sessions and coders necessary to obtain sufficiently stable estimates of these constructs. We used procedures derived from G theory to carry out a generalizability study, in which we partitioned error variance between two facets of our system for measuring joint engagement states : session and coder. A decision study was then conducted to determine the number of sessions and coders required to obtain g coefficients of 0.80, an a priori threshold set for acceptable stability. This process was conducted separately for 10 infant siblings of children with ASD (Sibs-ASD) and 10 infants whose older sibling did not have ASD (Sibs-TD), and for two different joint engagement states ; lower- and higher-order supported joint engagement (LSJE and HSJE, respectively). Results indicated that, in the Sibs-ASD group, four sessions and one coder was required to obtain acceptably stable estimates for HSJE ; only one session and one coder were required for LSJE. In the Sibs-TD group, two sessions and one coder were required for HSJE ; seven sessions and two coders were required for LSJE. Implications for measurement in future research are discussed. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : This study offers guidance for researchers who measure joint engagement between caregivers and infants who have an older sibling with ASD, and who have older siblings who are TD.

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6. Cage E, Troxell-Whitman Z. Understanding the Reasons, Contexts and Costs of Camouflaging for Autistic Adults. J Autism Dev Disord. 2019.

Camouflaging entails ’masking’ in or ’passing’ social situations. Research suggests camouflaging behaviours are common in autistic people, and may negatively impact mental health. To enhance understanding of camouflaging, this study examined reasons, contexts and costs of camouflaging. 262 autistic people completed measures of camouflaging behaviours, camouflaging contexts (e.g. work vs. family), camouflaging reasons (e.g. to make friends) and mental health symptoms. Findings indicated a gender difference in reasons for camouflaging, with autistic women more likely to endorse "conventional" reasons (e.g. getting by in formal settings such as work). Both camouflaging highly across contexts and ’switching’ between camouflaging in some contexts but not in others, related to poorer mental health. These findings have implications for understanding camouflaging in autistic adults.

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7. Carpenter KLH, Major S, Tallman C, Chen LW, Franz L, Sun J, Kurtzberg J, Song A, Dawson G. White Matter Tract Changes Associated with Clinical Improvement in an Open-Label Trial Assessing Autologous Umbilical Cord Blood for Treatment of Young Children with Autism. Stem cells translational medicine. 2019.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized by social communication deficits and the presence of restricted interests and repetitive behaviors. We have previously reported significant improvements in behavior, including increased social functioning, improved communication abilities, and decreased clinical symptoms in children with ASD, following treatment with a single infusion of autologous cord blood in a phase 1 open-label trial. In the current study, we aimed to understand whether these improvements were associated with concurrent changes in brain structural connectivity. Twenty-five 2- to 6-year-old children with ASD participated in this trial. Clinical outcome measures included the Vineland Adaptive Behavior Scales-II Socialization Subscale, Expressive One-Word Picture Vocabulary Test-4, and the Clinical Global Impression-Improvement Scale. Structural connectivity was measured at baseline and at 6 months in a subset of 19 children with 25-direction diffusion tensor imaging and deterministic tractography. Behavioral improvements were associated with increased white matter connectivity in frontal, temporal, and subcortical regions (hippocampus and basal ganglia) that have been previously shown to show anatomical, connectivity, and functional abnormalities in ASD. The current results suggest that improvements in social communication skills and a reduction in symptoms in children with ASD following treatment with autologous cord blood infusion were associated with increased structural connectivity in brain networks supporting social, communication, and language abilities. Stem Cells Translational Medicine 2019.

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8. Conlon O, Volden J, Smith IM, Duku E, Zwaigenbaum L, Waddell C, Szatmari P, Mirenda P, Vaillancourt T, Bennett T, Georgiades S, Elsabbagh M, Ungar WJ. Gender Differences in Pragmatic Communication in School-Aged Children with Autism Spectrum Disorder (ASD). J Autism Dev Disord. 2019.

Possible gender differences in manifestations of autism spectrum disorder (ASD) were examined using data on production of narratives. The Expression, Reception and Recall of Narrative Instrument (ERRNI ; Bishop, Expression, Reception and Recall of Narrative Instrument, Harcourt assessment, London, 2004) was administered to a sample of matched 8-year-old intellectually able boys and girls with ASD (13M, 13F), who had been selected from a large, longitudinal study. In addition, transcripts of the narratives were analyzed in detail. Significant gender differences were found in narrative production. Girls included more salient story elements than boys. On detailed language analysis, girls were also shown to tell richer stories, including more descriptors of planning or intention. Overall, our findings suggest that subtle differences in social communication may exist between intellectually able boys and girls with ASD. If reliably identifiable in young children, such gender differences may contribute to differential diagnosis of ASD. In addition, such differences may pave the way for differential approaches to intervention when the target is effective communication in sophisticated discourse contexts.

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9. Coretti L, Paparo L, Riccio MP, Amato F, Cuomo M, Natale A, Borrelli L, Corrado G, Comegna M, Buommino E, Castaldo G, Bravaccio C, Chiariotti L, Berni Canani R, Lembo F. Gut Microbiota Features in Young Children With Autism Spectrum Disorders. Frontiers in microbiology. 2018 ; 9 : 3146.

Proliferation and/or depletion of clusters of specific bacteria regulate intestinal functions and may interfere with neuro-immune communication and behavior in patients with autism spectrum disorder (ASD). Consistently, qualitative and quantitative alteration of bacterial metabolites may functionally affect ASD pathophysiology. Up to date, age-restricted cohort studies, that may potentially help to identify specific microbial signatures in ASD, are lacking. We investigated the gut microbiota (GM) structure and fecal short chain fatty acids (SCFAs) levels in a cohort of young children (2-4 years of age) with ASD, with respect to age-matched neurotypical healthy controls. Strong increase of Bacteroidetes and Proteobacteria and decrease of Actinobacteria was observed in these patients. Among the 91 OTUs whose relative abundance was altered in ASD patients, we observed a striking depletion of Bifidobacterium longum, one of the dominant bacteria in infant GM and, conversely, an increase of Faecalibacterium prausnitzii, a late colonizer of healthy human gut and a major butyrate producer. High levels of F. prausnitzii were associated to increase of fecal butyrate levels within normal range, and over representation of KEGG functions related to butyrate production in ASD patients. Here we report unbalance of GM structure with a shift in colonization by gut beneficial bacterial species in ASD patients as off early childhood.

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10. Costa AP, Steffgen G, Vogele C. The Role of Alexithymia in Parent-Child Interaction and in the Emotional Ability of Children with Autism Spectrum Disorder. Autism Res. 2019.

Children with autism spectrum disorder (ASD) have more emotional difficulties than typically developing (TD) children. Of all the factors that impact children’s emotional development, parents, and the way they interact with their children, are of crucial importance. The present study compared the amount of parent-child interactions among 35 dyads of parents and their children with ASD and 41 dyads of parents and their TD children, aged between 3 and 13 years, during a frustration-eliciting situation. We further examined whether children’s alexithymia is linked to parent-child interactions and whether parent-child interactions are linked to children’s emotional difficulties. We found that parents of children with ASD interacted significantly less with their children than parents of TD children. This reduced interaction was better explained by children’s alexithymia than by children’s ASD diagnosis. Finally, parent-child interaction mediated the relationship between children’s ASD diagnosis and children’s emotion regulation ability, as well as some aspects of children’s emotional reactivity but only if not accounting for children’s alexithymia levels. Our results demonstrate the determinant role children’s alexithymia plays on parent-child interactions and on how these interactions are linked to children’s difficulties in emotion regulation and emotional reactivity. Results are discussed in light of how parent-child interactions and the emotional ability of children with ASD can be improved by targeting children’s alexithymia. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : In the present research, we found that parents of children with autism interact less with their children compared to parents of typically developing children. We also found that this decreased interaction is linked to children’s difficulties to recognize, describe, and distinguish emotions, a triad of difficulties known as alexithymia. Furthermore, parents’ interaction with their children explains emotional reactivity and emotion regulation problems in children with autism. However, if we take into consideration children’s alexithymia, then parents’ interaction with their children is not related to their children’s emotional difficulties in reactivity and regulation. Therefore, to improve the interaction between parents and their children with autism, and the emotional development of these children, we recommend interventions that teach children with autism how to recognize, describe, and distinguish emotions in themselves and others.

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11. Davlantis KS, Estes A, Dawson G, Rogers SJ. A novel method for measuring learning opportunities provided by parents to young children with autism spectrum disorder. Autism. 2019 : 1362361318817303.

The aim of this study was to develop a measurement approach to assess the learning opportunities provided by parents to their young children with autism spectrum disorder during a free play task and to examine the relationship between learning opportunities and child performance on measures of cognition, autism spectrum disorder symptoms, and language. Participants were 91 children with autism spectrum disorder ages 12-24 months and their parents. Ordinary least squares regression was used. Results showed that children whose parents provided more learning opportunities had significantly higher cognitive scores and significantly higher vocabulary comprehension and production. The psychometric properties of the measurement approach were investigated and results indicated that it may be psychometrically sound.

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12. Del Bianco T, Mazzoni N, Bentenuto A, Venuti P. An Investigation of Attention to Faces and Eyes : Looking Time Is Task-Dependent in Autism Spectrum Disorder. Front Psychol. 2018 ; 9 : 2629.

A defective attention to faces and eyes characterizes autism spectrum disorder (ASD), however, the role of contingent information - such as the task instructions - remains still unclear. Our study aimed to investigate the face-orienting response and the subsequent attentive selection in the presence of varying task instructions in individuals with atypical and typical development. Twenty young adults with ASD and 24 young adults with typical development participated in our eye-tracking study. The participants received one of three different instructions at the beginning of each trial and watched scenes of a social interaction. The instructions asked either to find an object (visual-search, VS), to identify which actor was paying attention to the conversation (gaze-reading, GR), or to simply watch the video (free-viewing, FV). We found that the groups did not differ in terms of proportion of first fixations to the face. Nonetheless, average looking time and proportional looking time to faces differed across groups. Furthermore, proportional looking time to faces was task-dependent in the ASD group only, with maximum proportion in the GR and minimum in the VS condition. This result cannot be explained by a lack of an initial bias to orient to the face, since the face-orienting tendency was similar in the ASD and the control group.

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13. Fan Y, Du X, Liu X, Wang L, Li F, Yu Y. Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder. Front Genet. 2018 ; 9 : 665.

Autism spectrum disorder (ASD) is heterogeneous in symptom and etiology. Rare copy number variations (CNVs) are important genetic factors contributing to ASD. Currently chromosomal microarray (CMA) detecting CNVs is recommended as a first-tier diagnostic assay, largely based on research in North America and Europe. The feature of rare CNVs has not been well characterized in ASD cohorts from non-European ancestry. In this study, high resolution CMA was utilized to investigate rare CNVs in a Chinese cohort of ASD (n = 401, including 177 mildly/moderately and 224 severely affected individuals), together with an ancestry-matched control cohort (n = 197). Diagnostic yield was about 4.2%, with 17 clinically significant CNVs identified in ASD individuals, of which 12 CNVs overlapped with recurrent autism risk loci or genes. Autosomal rare CNV burden analysis showed an overrepresentation of rare loss events in ASD cohort, whereas the rate of rare gain events correlated with the phenotypic severity. Further analysis showed rare losses disrupting genes highly intolerant of loss-of-function variants were enriched in the ASD cohort. Among these highly constrained genes disrupted by rare losses, RIMS2 is a promising candidate contributing to ASD risk. This pilot study evaluated clinical utility of CMA and the feature of rare CNVs in Chinese ASD, with candidate genes identified as potential risk factors.

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14. Freitas BC, Mei A, Mendes APD, Beltrao-Braga PCB, Marchetto MC. Modeling Inflammation in Autism Spectrum Disorders Using Stem Cells. Front Pediatr. 2018 ; 6 : 394.

Recent reports show an increase in the incidence of Autism Spectrum Disorders (ASD) to 1 in every 59 children up to 8 years old in 11 states in North America. Induced pluripotent stem cell (iPSC) technology offers a groundbreaking platform for the study of polygenic neurodevelopmental disorders in live cells. Robust inflammation states and immune system dysfunctions are associated with ASD and several cell types participate on triggering and sustaining these processes. In this review, we will examine the contribution of neuroinflammation to the development of autistic features and discuss potential therapeutic approaches. We will review the available tools, emphasizing stem cell modeling as a technology to investigate the various molecular pathways and different cell types involved in the process of neuroinflammation in ASD.

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15. Fujiwara H, Yoshimura S, Kobayashi K, Ueno T, Oishi N, Murai T. Neural Correlates of Non-clinical Internet Use in the Motivation Network and Its Modulation by Subclinical Autistic Traits. Front Hum Neurosci. 2018 ; 12 : 493.

Background : Increasing evidence regarding the neural correlates of excessive or pathological internet use (IU) has accumulated in recent years, and comorbidity with depression and autism has been reported in multiple studies. However, psychological and neural correlates of non-clinical IU in healthy individuals remain unclear. Objectives : The aim of the current study was to investigate the relationships between non-clinical IU and functional connectivity (FC), focusing on the brain’s motivation network. We sought to clarify the influence of depression and autistic traits on these relationships in healthy individuals. Methods : Resting-state functional magnetic resonance imaging (fMRI) was performed in 119 healthy volunteers. IU, depression, and autistic traits were assessed using the Generalized Problematic Internet Use Scale 2 (GPIUS2), Beck Depression Inventory-II (BDI-II), and the autism spectrum quotient (AQ) scale, respectively. Correlational analyses were performed using CONN-software within the motivation-related network, which consisted of 22 brain regions defined by a previous response-conflict task-based fMRI study with a reward cue. We also performed mediation analyses via the bootstrap method. Results : Total GPIUS2 scores were positively correlated with FC between the (a) left middle frontal gyrus (MFG) and bilateral medial prefrontal cortex ; (b) left MFG and right supplementary motor area (SMA) ; (c) left MFG and right anterior insula, and (d) right MFG and right insula. The "Mood Regulation" subscale of the GPIUS2 was positively correlated with FC between left MFG and right SMA. The "Deficient Self-Regulation" subscale was positively correlated with FC between right MFG and right anterior insula (statistical thresholds, FDR < 0.05). Among these significant correlations, those between GPIUS2 (total and "Mood Regulation" subscale) scores and FC became stronger after controlling for AQ scores (total and "Attention Switching" subscale), indicating significant mediation by AQ (95% CI < 0.05). In contrast, BDI-II had no mediating effect. Conclusion : Positive correlations between IU and FC in the motivation network may indicate health-promoting effects of non-clinical IU. However, this favorable association is attenuated in individuals with subclinical autistic traits, suggesting the importance of a personalized educational approach for these individuals in terms of adequate IU.

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16. Hu X, Han ZR, Wang H, Hu Y, Wang Q, Feng S, Yi L. The Relation of Parental Emotion Regulation to Child Autism Spectrum Disorder Core Symptoms : The Moderating Role of Child Cardiac Vagal Activity. Front Psychol. 2018 ; 9 : 2480.

This study investigated the role of parental emotion regulation (ER) on children’s core symptoms in families of children with autism spectrum disorders (ASD) in middle childhood ; the study also explored whether children’s physiological ER functioning served as a risk or protective factor with respect to parental relationships. Thirty-one Chinese children with ASD (age 6-11) and their primary caregivers participated in this study. Parental ER and child ASD symptoms were collected via questionnaires from parents. Child cardiac vagal activity (derived from heart rate variability) was measured at rest and during a parent-child interaction task. Using moderation analyses, the results showed that parental ER was not directly associated with children’s core ASD symptoms ; rather, it interacted significantly with children’s resting cardiac vagal activity, but not task-related changes of cardiac vagal activity, to exert an impact on children’s core ASD symptoms. Specifically, our findings suggested that parents’ difficulties with their own ER significantly impacted their children’s core ASD symptoms only for the children who showed blunted resting cardiac vagal activity. Implications for the future measurement of ER in the family context and future directions for intervention are discussed.

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17. Kellerman AM, Schwichtenberg AJ, Tonnsen BL, Posada G, Lane SP. Dyadic interactions in children exhibiting the broader autism phenotype : Is the broader autism phenotype distinguishable from typical development ?. Autism Res. 2019.

In families raising a child with an autism spectrum disorder (ASD), infant siblings are at elevated risk for ASD and other developmental concerns, including elements of the broader autism phenotype (BAP). Typically, the BAP is indexed using standardized developmental assessments ; however, these measures do not capture a number of social difficulties commonly associated with the BAP. The present study aims to expand our developmental understanding of the BAP by comparing children exhibiting the BAP to their typically developing peers on, (a) standardized measures of development, and (b) social behaviors exhibited during dyadic play interactions. As part of a prospective study, dyads were recruited from families with at least one older child with ASD (high-risk, n = 36), and families with no history of ASD (low-risk, n = 38). During laboratory visits at 12, 15, 18, and 24 months of age, infants completed a series of standardized assessments and a mother-child play interaction. Dyadic play interactions were micro-analytically coded for gaze, positive affect, and vocalizations to create theory-driven composites to index dyadic synchrony and responsiveness. Videos were also coded with an existing rating scheme for joint engagement and child responsiveness. Multilevel models revealed significant group differences on select constructs within the first 2 years. Language and cognitive differences emerged by 24 months of age, whereas dyadic differences were evident as early as 15 months. Recognizing the increasing demand for elevated-risk interventions, these findings highlight several social constructs through which interventions may identify risk and promote optimal development. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : In families raising children with an autism spectrum disorder (ASD), younger siblings are at an increased risk for social and developmental difficulties that characterize a "broader autism phenotype." The present study explored the emergence of social, language, and cognitive differences in the first 2 years of life. Social differences were evident as early as 15 months of age for several play-based measures, and language and cognitive differences emerged by 24 months of age. For infant siblings of children with ASD, some of the earliest behavioral marks for subclinical features of ASD are evident within the first 2 years of life.

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18. Krupa M, Boominathan P, Ramanan PV, Sebastian S. Relationship Between Screen Time and Mother-Child Reciprocal Interaction in Typically Developing Children and Children with Autism Spectrum Disorders. Indian journal of pediatrics. 2019.

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19. Li T, Decety J, Hu X, Li J, Lin J, Yi L. Third-Party Sociomoral Evaluations in Children With Autism Spectrum Disorder. Child Dev. 2019.

We examined explicit and implicit processes in response to third-party moral transgressions in children with autism spectrum disorder (ASD). Twenty 4- to 7-year-old children with ASD and 19 typically developing controls evaluated dynamic visual stimuli depicting intentional or accidental harm to persons or damage to objects. Moral evaluations, eye fixations, and pupil dilations toward the stimuli were collected. Results indicate a preserved capacity to understand the mental states of perpetrators and an implicit moral sensitivity to the third-party harms in children with ASD. Nonetheless, children with ASD showed specific sensitivity and emotional arousal when viewing damage to objects. These findings contribute to the understanding of the underlying mechanisms of moral reasoning in ASD and its possible association with the autistic symptoms.

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20. Lombardo MV, Lai MC, Baron-Cohen S. Big data approaches to decomposing heterogeneity across the autism spectrum. Mol Psychiatry. 2019.

Autism is a diagnostic label based on behavior. While the diagnostic criteria attempt to maximize clinical consensus, it also masks a wide degree of heterogeneity between and within individuals at multiple levels of analysis. Understanding this multi-level heterogeneity is of high clinical and translational importance. Here we present organizing principles to frame research examining multi-level heterogeneity in autism. Theoretical concepts such as ’spectrum’ or ’autisms’ reflect non-mutually exclusive explanations regarding continuous/dimensional or categorical/qualitative variation between and within individuals. However, common practices of small sample size studies and case-control models are suboptimal for tackling heterogeneity. Big data are an important ingredient for furthering our understanding of heterogeneity in autism. In addition to being ’feature-rich’, big data should be both ’broad’ (i.e., large sample size) and ’deep’ (i.e., multiple levels of data collected on the same individuals). These characteristics increase the likelihood that the study results are more generalizable and facilitate evaluation of the utility of different models of heterogeneity. A model’s utility can be measured by its ability to explain clinically or mechanistically important phenomena, and also by explaining how variability manifests across different levels of analysis. The directionality for explaining variability across levels can be bottom-up or top-down, and should include the importance of development for characterizing changes within individuals. While progress can be made with ’supervised’ models built upon a priori or theoretically predicted distinctions or dimensions of importance, it will become increasingly important to complement such work with unsupervised data-driven discoveries that leverage unknown and multivariate distinctions within big data. A better understanding of how to model heterogeneity between autistic people will facilitate progress towards precision medicine for symptoms that cause suffering, and person-centered support.

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21. London EB. Neuromodulation and a Reconceptualization of Autism Spectrum Disorders : Using the Locus Coeruleus Functioning as an Exemplar. Frontiers in neurology. 2018 ; 9 : 1120.

The Autism Spectrum Disorders (ASD) are a heterogeneous group of developmental disorders. Although, ASD can be reliably diagnosed, the etiology, pathophysiology, and treatment targets remain poorly characterized. While there are many atypical findings in anatomy, genetics, connectivity, and other biologic parameters, there remains no discreet hypothesis to explain the core signs as well as the very frequent comorbidities. Due to this, designing targets for treatments can only be done by assuming each symptom is a result of a discreet abnormality which is likely not the case. Neuronal circuity remains a major focus of research but rarely taking into account the functioning of the brain is highly dependent on various systems, including the neuromodulatory substances originating in the midbrain. A hypothesis is presented which explores the possibility of explaining many of the symptoms found in ASD in terms of inefficient neuromodulation using the functioning of the locus coeruleus and norepinephrine (LC/NE) as exemplars. The basic science of LC/NE is reviewed. Several functions found to be impaired in ASD including learning, attention, sensory processing, emotional regulation, autonomic functioning, adaptive and repetitive behaviors, sleep, language acquisition, initiation, and prompt dependency are examined in terms of the functioning of the LC/NE system. Suggestions about possible treatment directions are explored.

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22. Masataka N. Neurodiversity and Artistic Performance Characteristic of Children With Autism Spectrum Disorder. Front Psychol. 2018 ; 9 : 2594.

Neurodiversity refers to the notion that seemingly ’impaired’ cognitive as well as emotional features characteristic of developmental disorders such as autism spectrum disorder (ASD) fall into normal human behavioral variations that should enjoy some selective advantages. In the present experiment, the author compared what was depicted in subjects’ drawings after they experienced an identical event, e.g., going on a picnic to a garden in the vicinity of their nursery school, between children with ASD and IQ-matched, typically developing (TD) children. When the material was coded according to types of drawn objects, such as human, animal, plant, food, vehicle, building, and others, the overall variability of the objects did not differ between TD children and children with ASD. However, TD children were more likely than children with ASD to depict human images. Conversely, other objects were more likely to be drawn by children with ASD than by TD children. While TD children were more likely to focus on humans than on non-human objects when drawing, children with ASD were more likely to focus on non-human objects than on humans even after both had experienced an identical event. The author argues that such findings are empirical evidence for the claim that there is some selective advantage of enhanced capabilities characteristic of ASD, i.e., neurodiversity, that may represent a balance toward "folk physics" at the expense of "folk psychology."

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23. Maurin T, Bardoni B. Fragile X Mental Retardation Protein : To Be or Not to Be a Translational Enhancer. Frontiers in molecular biosciences. 2018 ; 5 : 113.

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24. Maximo JO, Kana RK. Aberrant "deep connectivity" in autism : A cortico-subcortical functional connectivity magnetic resonance imaging study. Autism Res. 2019.

The number of studies examining functional brain networks in Autism Spectrum Disorder (ASD) has risen over the last decade and has characterized ASD as a disorder of altered brain connectivity. However, these studies have focused largely on cortical structures, and only a few studies have examined cortico-subcortical connectivity in regions like thalamus and basal ganglia in ASD. The goal of this study was to characterize the functional connectivity between cortex and subcortical regions in ASD using the Autism Brain Imaging Data Exchange (ABIDE-II). Resting-state functional magnetic resonance imaging data were used from 168 typically developing (TD) and 138 ASD participants across different sites from the ABIDE II dataset. Functional connectivity of basal ganglia and thalamus to unimodal and supramodal networks was examined in this study. Overconnectivity (ASD > TD) was found between unimodal (except for medial visual network) and subcortical regions, and underconnectivity (TD > ASD) was found between supramodal (except for default mode and dorsal attention networks) and subcortical regions ; positive correlations between ASD phenotype and unimodal-subcortical connectivity were found and negative ones with supramodal-subcortical connectivity. These findings suggest that brain networks heavily involved in sensory processing had higher connectivity with subcortical regions, whereas those involved in higher-order thinking showed decreased connectivity in ASD. In addition, brain-behavior correlations indicated a relationship between ASD phenotype and connectivity. Thus, differences in cortico-subcortical connectivity may have a significant impact on basic and higher-order cognitive processes in ASD. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : This study focused on examining the functional connectivity (synchronization of brain activity across regions) of two types of brain networks (unimodal and supramodal) with subcortical areas (thalamus and basal ganglia) in children, adolescents, and adults with autism spectrum disorder (ASD) and how this relates to ASD phenotype. ASD participants showed overconnectivity in unimodal networks and underconnectivity in supramodal networks. These findings provide new insights into cortico-subcortical connections between basic sensory and high-order cognitive processes.

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25. Olson CO, Pejhan S, Kroft D, Sheikholeslami K, Fuss D, Buist M, Ali Sher A, Del Bigio MR, Sztainberg Y, Siu VM, Ang LC, Sabourin-Felix M, Moss T, Rastegar M. MECP2 Mutation Interrupts Nucleolin-mTOR-P70S6K Signaling in Rett Syndrome Patients. Front Genet. 2018 ; 9 : 635.

Rett syndrome (RTT) is a severe and rare neurological disorder that is caused by mutations in the X-linked MECP2 (methyl CpG-binding protein 2) gene. MeCP2 protein is an important epigenetic factor in the brain and in neurons. In Mecp2-deficient neurons, nucleoli structures are compromised. Nucleoli are sites of active ribosomal RNA (rRNA) transcription and maturation, a process mainly controlled by nucleolin and mechanistic target of rapamycin (mTOR)-P70S6K signaling. Currently, it is unclear how nucleolin-rRNA-mTOR-P70S6K signaling from RTT cellular model systems translates into human RTT brain. Here, we studied the components of nucleolin-rRNA-mTOR-P70S6K signaling in the brain of RTT patients with common T158M and R255X mutations. Immunohistochemical examination of T158M brain showed disturbed nucleolin subcellular localization, which was absent in Mecp2-deficient homozygous male or heterozygote female mice, compared to wild type (WT). We confirmed by Western blot analysis that nucleolin protein levels are altered in RTT brain, but not in Mecp2-deficient mice. Further, we studied the expression of rRNA transcripts in Mecp2-deficient mice and RTT patients, as downstream molecules that are controlled by nucleolin. By data mining of published ChIP-seq studies, we showed MeCP2-binding at the multi-copy rRNA genes in the mouse brain, suggesting that rRNA might be a direct MeCP2 target gene. Additionally, we observed compromised mTOR-P70S6K signaling in the human RTT brain, a molecular pathway that is upstream of rRNA-nucleolin molecular conduits. RTT patients showed significantly higher phosphorylation of active mTORC1 or mTORC2 complexes compared to age- and sex-matched controls. Correlational analysis of mTORC1/2-P70S6K signaling pathway identified multiple points of deviation from the control tissues that may result in abnormal ribosome biogenesis in RTT brain. To our knowledge, this is the first report of deregulated nucleolin-rRNA-mTOR-P70S6K signaling in the human RTT brain. Our results provide important insight toward understanding the molecular properties of human RTT brain.

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26. Russell NCC, Luke SG, Lundwall RA, South M. Not So Fast : Autistic traits and Anxious Apprehension in Real-World Visual Search Scenarios. J Autism Dev Disord. 2019.

Autistic individuals have shown superior performance in simple, albeit difficult, visual search tasks. We compared eye movements and behavioral markers across two visual search tasks based on real-world scenes in young adults. Context-aided search increased speed and accuracy for all groups. Autistic adults (n = 29) were on average consistently slower and less accurate than a non-anxious neurotypical comparison group (n = 48), but similar to neurotypical adults with elevated anxious apprehension (n = 26). Dimensional analyses suggest that autism traits, not anxious apprehension, are most associated with search efficiency of naturalistic stimuli suggesting that autistic individuals can effectively integrate contextual information to aid visual search, but that advantages in less visually complex tasks, reported in previous studies, may not transfer to situations involving real-world scenes.

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27. Sanchez-Garcia AB, Galindo-Villardon P, Nieto-Librero AB, Martin-Rodero H, Robins DL. Toddler Screening for Autism Spectrum Disorder : A Meta-Analysis of Diagnostic Accuracy. J Autism Dev Disord. 2019.

Great efforts focus on early detection of autism spectrum disorder, although some scientists and policy-makers have questioned early universal screening. The aim of this meta-analysis was to evaluate the diagnostic accuracy of the different screening tools. Several electronic databases were used to identify published studies. A Bayesian model was used to estimate the screening accuracy. The pooled sensitivity was 0.72 (95% CI 0.61-0.81), and the specificity was 0.98 (95% CI 0.97-0.99). Subgroup analyses to remove heterogeneity indicated sensitivity was 0.77 (95% CI 0.69-0.84), and specificity was 0.99 (95% CI 0.97-0.99 ; SD </= 0.01). Level 1 screening tools for ASD showed consistent statistically significant results and therefore are adequate to detect autism at 14-36 months.

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28. Sanctuary MR, Kain JN, Chen SY, Kalanetra K, Lemay DG, Rose DR, Yang HT, Tancredi DJ, German JB, Slupsky CM, Ashwood P, Mills DA, Smilowitz JT, Angkustsiri K. Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS One. 2019 ; 14(1) : e0210064.

Over half of all children with autism spectrum disorders (ASD) have gastrointestinal (GI) co-morbidities including chronic constipation, diarrhea, and irritable bowel syndrome. The severity of these symptoms has been correlated with the degree of GI microbial dysbiosis. The study objective was to assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities. This pilot study is a randomized, double blind, controlled trial of combination treatment (BCP + B. infantis) vs. BCP alone in a cross-over study in children ages 2-11 with ASD and GI co-morbidities (n = 8). This 12-week study included 5 weeks of probiotic-prebiotic supplementation, followed by a two-week washout period, and 5 weeks of prebiotic only supplementation. The primary outcome of tolerability was assessed using validated questionnaires of GI function and atypical behaviors, along with side effects. Results suggest that the combination treatment is well-tolerated in this cohort. The most common side effect was mild gassiness. Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors. Improvement may be explained by a reduction in IL-13 and TNF-alpha production in some participants. Although limited conclusions can be drawn from this small pilot study, the results support the need for further research into the efficacy of these treatments.

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29. Schafer ST, Paquola ACM, Stern S, Gosselin D, Ku M, Pena M, Kuret TJM, Liyanage M, Mansour AA, Jaeger BN, Marchetto MC, Glass CK, Mertens J, Gage FH. Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons. Nat Neurosci. 2019.

Autism spectrum disorder (ASD) is thought to emerge during early cortical development. However, the exact developmental stages and associated molecular networks that prime disease propensity are elusive. To profile early neurodevelopmental alterations in ASD with macrocephaly, we monitored subject-derived induced pluripotent stem cells (iPSCs) throughout the recapitulation of cortical development. Our analysis revealed ASD-associated changes in the maturational sequence of early neuron development, involving temporal dysregulation of specific gene networks and morphological growth acceleration. The observed changes tracked back to a pathologically primed stage in neural stem cells (NSCs), reflected by altered chromatin accessibility. Concerted over-representation of network factors in control NSCs was sufficient to trigger ASD-like features, and circumventing the NSC stage by direct conversion of ASD iPSCs into induced neurons abolished ASD-associated phenotypes. Our findings identify heterochronic dynamics of a gene network that, while established earlier in development, contributes to subsequent neurodevelopmental aberrations in ASD.

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30. Shire SY, Shih W, Chang YC, Bracaglia S, Kodjoe M, Kasari C. Sustained Community Implementation of JASPER Intervention with Toddlers with Autism. J Autism Dev Disord. 2019.

Intervention research is increasingly conducted in community settings, however it is not clear how well practices are sustained locally or how children progress once external research support is removed. Two school-year cohorts of toddlers with autism (year 1 : n = 55, year 2 : n = 63) received Joint Attention, Symbolic Play, Engagement, and Regulation (JASPER) intervention from teaching assistants (TAs) with external support in year 1 and local, internal support in year 2. TAs sustained intervention strategies with more modest maintenance of high-level skills. Children in both years 1 and 2 made similar gains in initiations of joint attention during independent assessment. Year 1 children made significantly greater play gains. JASPER sustained into year 2, however advancing play may require additional supports.

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31. Vargason T, Kruger U, Roth E, Delhey LM, Tippett M, Rose S, Bennuri SC, Slattery JC, Melnyk S, James SJ, Frye RE, Hahn J. Comparison of Three Clinical Trial Treatments for Autism Spectrum Disorder Through Multivariate Analysis of Changes in Metabolic Profiles and Adaptive Behavior. Frontiers in cellular neuroscience. 2018 ; 12 : 503.

Several studies associate autism spectrum disorder (ASD) pathophysiology with metabolic abnormalities related to DNA methylation and intracellular redox homeostasis. In this regard, three completed clinical trials are reexamined in this work : treatment with (i) methylcobalamin (MeCbl) in combination with low-dose folinic acid (LDFA), (ii) tetrahydrobiopterin, and (iii) high-dose folinic acid (HDFA) for counteracting abnormalities in the folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) pathways and also for improving ASD-related symptoms and behaviors. Although effects of treatment on individual metabolites and behavioral measures have previously been investigated, this study is the first to consider the effect of interventions on a set of metabolites of the FOCM/TS pathways and to correlate FOCM/TS metabolic changes with behavioral improvements across several studies. To do so, this work uses data from one case-control study and the three clinical trials to develop multivariate models for considering these aspects of treatment. Fisher discriminant analysis (FDA) is first used to establish a model for distinguishing individuals with ASD from typically developing (TD) controls, which is subsequently evaluated on the three treatment data sets, along with one data set for a placebo, to characterize the shift of FOCM/TS metabolism toward that of the TD population. Treatment with MeCbl plus LDFA and, separately, treatment with tetrahydrobiopterin significantly shifted the metabolites toward the values of the control group. Contrary to this, treatment with HDFA had a lesser, though still noticeable, effect whilst the placebo group showed marginal, but not insignificant, variations in metabolites. A second analysis is then performed with non-linear kernel partial least squares (KPLS) regression to predict changes in adaptive behavior, quantified by the Vineland Adaptive Behavior Composite, from changes in FOCM/TS biochemical measurements provided by treatment. Incorporating the 74 samples receiving any treatment, including placebo, into the regression analysis yields an R (2) of 0.471 after cross-validation when using changes in six metabolic measurements as predictors. These results are suggestive of an ability to effectively improve pathway-wide FOCM/TS metabolic and behavioral abnormalities in ASD with clinical treatment.

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32. Zhou Y, Zhang L, Teng S, Qiao L, Shen D. Improving Sparsity and Modularity of High-Order Functional Connectivity Networks for MCI and ASD Identification. Front Neurosci. 2018 ; 12 : 959.

High-order correlation has recently been proposed to model brain functional connectivity network (FCN) for identifying neurological disorders, such as mild cognitive impairment (MCI) and autism spectrum disorder (ASD). In practice, the high-order FCN (HoFCN) can be derived from multiple low-order FCNs that are estimated separately in a series of sliding windows, and thus it in fact provides a way of integrating dynamic information encoded in a sequence of low-order FCNs. However, the estimation of low-order FCN may be unreliable due to the fact that the use of limited volumes/samples in a sliding window can significantly reduce the statistical power, which in turn affects the reliability of the resulted HoFCN. To address this issue, we propose to enhance HoFCN based on a regularized learning framework. More specifically, we first calculate an initial HoFCN using a recently developed method based on maximum likelihood estimation. Then, we learn an optimal neighborhood network of the initially estimated HoFCN with sparsity and modularity priors as regularizers. Finally, based on the improved HoFCNs, we conduct experiments to identify MCI and ASD patients from their corresponding normal controls. Experimental results show that the proposed methods outperform the baseline methods, and the improved HoFCNs with modularity prior consistently achieve the best performance.

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